ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.838C>T (p.Arg280Cys) (rs199840380)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160755 SCV000211409 uncertain significance not provided 2018-10-09 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.880C>T at the cDNA level, p.Arg294Cys (R294C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been identified in an individual with breast cancer (Liu 2017). MUTYH Arg294Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the APE1 binding domain (Parker 2001, Yang 2001). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MUTYH Arg294Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two MUTYH pathogenic variants on opposite chromosomes.
Ambry Genetics RCV000214420 SCV000274835 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-14 criteria provided, single submitter clinical testing The p.R294C variant (also known as c.880C>T), located in coding exon 10 of the MUTYH gene, results from a C to T substitution at nucleotide position 880. The arginine at codon 294 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a Chinese patient with triple-negative breast cancer (Liu X et al. Cancer Med. 2017 Mar;6:547-554). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000459211 SCV000545786 uncertain significance MYH-associated polyposis 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 294 of the MUTYH protein (p.Arg294Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199840380, ExAC 0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 28135048). ClinVar contains an entry for this variant (Variation ID: 182692). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C1). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5
Color Health, Inc RCV000214420 SCV000685677 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-10 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 294 of the MUTYH protein. This variant is known as c.838C>T (p.Arg280Cys) based on the alternate NM_001048171.1 transcript. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145) and breast cancer (PMID: 28135048). This variant has been identified in 7/245982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl RCV000459211 SCV000793524 uncertain significance MYH-associated polyposis 2017-08-24 criteria provided, single submitter clinical testing
GeneKor MSA RCV000214420 SCV000822080 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000160755 SCV001147267 uncertain significance not provided 2019-03-01 criteria provided, single submitter clinical testing

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